Despite progress in planning and delivery of radiation therapy, treatment of abdominal tumors is dose-limited by the risk of intestinal toxicity (radiation enteropathy). The previous notion that radiation enteropathy develops exclusively as a result of crypt cell death has been supplanted. Instead, it is now widely recognized that many functional and secondary changes contribute to the manifestations of radiation enteropathy. These changes are promising targets for interventions to prevent and/or reduce radiation-induced bowel toxicity. In the intestine, there are important connections between the nervous system and cells of the immune system. Notably, sensory nerves and resident mast cells in the bowel mucosa constitute a functional unit that regulates many physiological and pathological processes through bidirectional interactions. We have shown that crosstalk between intestinal sensory nerves and mast cells substantially regulate the development of radiation enteropathy. The extension of this MERIT award will use validated genetic and phannacologic approaches, coupled with quantitative structural and functional endpoints and molecular methods, to systematically dissect the mechanisms by which these neuroimmune interactions modulate the intestinal radiation response. We will 1) examine the role ofthe endocannabinoid system and its relationship to mast cells and sensory neurons in early and delayed radiation enteropathy; 2) determine to what extent the kinin- kallikrein system regulates radiation enteropathy development and whether the effects depend on resident mast cells or sensory nerves; and 3) investigate the significance of the sympathetic nervous system in radiation enteropathy. These experiments are based on data generated during the previous funding period and will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. Advancing the understanding ofthe basic mechanisms underlying radiation enteropathy is critical for identifying targets for intervention. This research will thus facilitate development of specific strategies to minimize intestinal radiation toxicity in the clinic and thereby make radiation therapy safer and more effective.